rs758155107

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_001377.3(DYNC2H1):​c.7945G>T​(p.Gly2649Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,611,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DYNC2H1
NM_001377.3 missense

Scores

11
7
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 9.90
Variant links:
Genes affected
DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a region_of_interest AAA 4 (size 246) in uniprot entity DYHC2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001377.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.912
PP5
Variant 11-103199333-G-T is Pathogenic according to our data. Variant chr11-103199333-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446617.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYNC2H1NM_001080463.2 linkc.7945G>T p.Gly2649Cys missense_variant Exon 49 of 90 ENST00000650373.2 NP_001073932.1 Q8NCM8-2
DYNC2H1NM_001377.3 linkc.7945G>T p.Gly2649Cys missense_variant Exon 49 of 89 ENST00000375735.7 NP_001368.2 Q8NCM8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DYNC2H1ENST00000650373.2 linkc.7945G>T p.Gly2649Cys missense_variant Exon 49 of 90 NM_001080463.2 ENSP00000497174.1 Q8NCM8-2
DYNC2H1ENST00000375735.7 linkc.7945G>T p.Gly2649Cys missense_variant Exon 49 of 89 1 NM_001377.3 ENSP00000364887.2 Q8NCM8-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
248582
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134824
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000355
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000754
AC:
11
AN:
1459780
Hom.:
0
Cov.:
31
AF XY:
0.00000551
AC XY:
4
AN XY:
726170
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:3
Pathogenic, no assertion criteria providedresearchDan Cohn Lab, University Of California Los AngelesJun 01, 2017- -
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 14, 2024This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2649 of the DYNC2H1 protein (p.Gly2649Cys). This variant is present in population databases (rs758155107, gnomAD 0.004%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 446617). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC2H1 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Gly2649 amino acid residue in DYNC2H1. Other variant(s) that disrupt this residue have been observed in individuals with DYNC2H1-related conditions (PMID: 34918830), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.56
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;D;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
.;D;.;D
M_CAP
Pathogenic
0.45
D
MetaRNN
Pathogenic
0.91
D;D;D;D
MetaSVM
Uncertain
0.13
D
MutationAssessor
Pathogenic
3.7
H;H;H;H
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-7.4
D;.;.;D
REVEL
Uncertain
0.62
Sift
Pathogenic
0.0
D;.;.;D
Sift4G
Uncertain
0.0020
D;.;.;D
Polyphen
1.0
D;D;D;D
Vest4
0.97
MutPred
0.70
Loss of disorder (P = 0.0596);Loss of disorder (P = 0.0596);Loss of disorder (P = 0.0596);Loss of disorder (P = 0.0596);
MVP
0.85
MPC
0.40
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.96
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.61
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.61
Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs758155107; hg19: chr11-103070062; API